Key Event Component

Key Event Overview

AOPs Including This Key Event

Stressors

Level of Biological Organization

Taxonomic Applicability

Life Stages

Sex Applicability

How This Key Event Works

The occurrence of altered hepatic foci (AHF) as precursors to liver tumors in AFB1-treated rats has been recognized for decades. Originally, these foci were observed as histologically different from the surrounding parenchyma. (Harada et al, 1989, 1990; Gil et al., 1988; Bannasch et al., 1985) In addition, enzyme alterations were used to identify AHF foci, most notably, the occurrence of a placental form of glutathione-S-transferase (GSTP+). (Godlewski et al., 1985; Dragan et al., 1994a, 1995; Kirby et al., 1990) The growth and occurrence of foci are expressed as the number of AHF in a volume of liver, possibly the entire liver, and the volume fraction of the liver occupied by AHF. (Dragan et al., 1997) Both of these reflect focal growth because single cell foci are not detectable with the immunohistochemical staining technique. The assumption is that single transformed cells in which apoptosis is blocked by tumor-critical mutations will grow into AHF. (Grassl-Kraupp et al., 1997). A number of agents regarded as tumor promoters appear to enhance the growth of foci, acting to further inhibit apoptosis and also creating an overall proliferative stimulus. (Angsubhakorn et al., 2002; Wyde et al., 2002).

AFB1 appears to be a “complete” carcinogen in that the toxin acts as an initiator through the formation of pro-mutagenic DNA adducts (the MIE) and as a promoter through increasing oxidative stress and inflammation. (Ohnishi et al., 2013; Caballero et al., 2004).

Evidence Supporting Essentiality

Strong

Chemoprevention studies, reviewed in another section of this AOP, suggest a strong relationship between altered hepatic foci (AHF) and HCC tumor formation (Olden and Vulimiri, 2014; Liby et al., 2008; Yates et al., 2007; Yates and Kensler, 2007; Kensler et al., 2004). For example, Johnson et al. (2014) observed background levels of AHF along with a complete absence of tumors in rats treated with a triterpenoid chemoprotectant CDDO-Im, despite maintaining a significant burden of AFB1-induced adducts. (Johnson et al., 2014) Cell proliferation appears to be six- to seven-fold greater in AHF than in surrounding liver parenchyma. (Dragan et al., 1994) However, the measurements were made from liver biopsies, and whether the increased expression was associated with foci is not known.

Xu YH, Maronpot R, Pitot HC (1990) Quantitative stereologic study of the effects of varying the time between initiation and promotion on four histochemical markers in rat liver during hepatocarcinogenesis. Carcinogenesis 11: 267-272.

Xu YH, Campbell HA, Sattler GL, Hendrich S, Maronpot R, et al (1990) Quantitative stereological analysis of the effects of age and sex on multistage hepatocarcinogenesis in the rat by use of four cytochemical markers. Cancer Res 50: 472-479.